Farnesyl transferase inhibiting 6-heterocyclylmethyl quinoline and quinazoline derivatives

ABSTRACT

This invention comprises the novel compounds of formula (I) 
                         
wherein r, t, Y 1 —Y 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  have defined meanings, having farnesyl transferase inhibiting activity; their preparation, compositions containing them and their use as a medicine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of Application No. PCT/EP018945,filed Sep. 18, 2001 which application claims priority from EP 00203368.6filed Sep. 25, 2000, and EP 01202190.3 filed Jun. 7, 2001.

The present invention is concerned with novel 6-heterocyclylmethylquinoline and quinazoline derivatives, the preparation thereof,pharmaceutical compositions comprising said novel compounds and the useof these compounds as a medicine as well as methods of treatment byadministering said compounds.

Oncogenes frequently encode protein components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer. A particular groupof oncogenes is known as ras which have been identified in mammals,birds, insects, mollusks, plants, fungi and yeasts. The family ofmammalian ras oncogenes consists of three major members (“isoforms”):H-ras, K-ras and N-ras oncogenes. These ras oncogenes code for highlyrelated proteins generically known as p21^(ras). Once attached to plasmamembranes, the mutant or oncogenic forms of p21^(ras) will provide asignal for the transformation and uncontrolled growth of malignant tumorcells. To acquire this transforming potential, the precursor of thep21^(ras) oncoprotein must undergo an enzymatically catalyzedfarnesylation of the cysteine residue located in a carboxyl-terminaltetrapeptide. Therefore, inhibitors of the enzymes that catalyzes thismodification, i.e. farnesyl transferase, will prevent the membraneattachment of p21^(ras) and block the aberrant growth of ras-transformedtumors. Hence, it is generally accepted in the art that farnesyltransferase inhibitors can be very useful as anticancer agents fortumors in which ras contributes to transformation.

Since mutated oncogenic forms of ras are frequently found in many humancancers, most notably in more than 50% of colon and pancreaticcarcinomas (Kohl et al., Science, vol 260, 1834–1837, 1993), it has beensuggested that farnesyl tranferase inhibitors can be very useful againstthese types of cancer.

In EP-0,371,564 there are described (1H-azol-1-ylmethyl) substitutedquinoline and quinolinone derivatives which suppress the plasmaelimination of retinoic acids. Some of these compounds also have theability to inhibit the formation of androgens from progestines and/orinhibit the action of the aromatase enzyme complex.

In WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157, there aredescribed 2-quinolinones and 2-quinazolinones derivatives which exhibitfarnesyl transferase inhibiting activity. WO 00/39082 describes a classof novel 1,2-annelated quinoline compounds, bearing a nitrogen- orcarbon-linked imidazole, which show farnesyl protein transferase andgeranylgeranyl transferase inhibiting activity. Other quinolonecompounds having farnesyl transferase inhibiting activity are describedin WO 00/12498, 00/12499 and 00/47574.

Unexpectedly, it has been found that the present novel6-heterocyclylmethyl quinoline and quinazoline compounds show farnesylprotein transferase inhibiting activity.

The present invention concerns compounds of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein

-   r is 0, 1, 2, 3, 4 or 5;-   t is 0, 1, 2 or 3;-   >Y¹—Y²—is a trivalent radical of formula

>C═N— (y-1) >C═CR⁹— (y-2) >CH—NR⁹— (y-3) >CH—CHR⁹— (y-4)

-   wherein R⁹ is hydrogen, halo, cyano, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, C₁₋₆alkyloxy, halocarbonyl, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, aryl or a group of formula —NR²²R²³,    —C₁₋₆alkyl-NR²²R²³, —C₂₋₆alkenyl-NR²²R²³, —CONR²²R²³ or    —NR²²—C₁₋₆alkyl-NR²²R²³;    -   p is 0 to 5;    -   R²⁰ and R²¹ are independently hydrogen or C₁₋₆ alkyl and are        independently defined for each iteration of p in excess of 1;    -   R²² and R²³ are independently hydrogen, C₁₋₆ alkyl or        —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or together with the adjacent        nitrogen atom form a 5- or 6-membered heterocyclic ring        optionally containing one, two or three further heteroatoms        selected from oxygen, nitrogen or sulphur and optionally        substituted by one or two substituents each independently        selected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl,        haloC₁₋₆alkyl, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl, aminocarbonyl, mono- or        di-(C₁₋₆alkyl)aminocarbonyl, amino, mono- or di(C₁₋₆alkyl)amino,        C₁₋₆alkylsulfonylamino, oxime, or phenyl;-   R¹ is azido, hydroxy, halo, cyano, nitro, C₁₋₆alkyl,    —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyloxyC₁₋₆alkyl, R²⁴S    C₁₋₆alkyl, trihalomethyl, arylC₁₋₆alkyl, Het²C₁₋₆alkyl,    —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkylNR²²C₁₋₆alkyl-NR²²R²³,    —C₁₋₆alkylNR²²COC₁₋₆alkyl, —C₁₋₆alkylNR²²COAlkAr²,    —C₁₋₆alkylNR²²COAr², C₁₋₆alkylsulphonylaminoC₁₋₆alkyl, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, —OC₁₋₆alkyl-NR²²R²³,    trihalomethoxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, C₁₋₆alkylthio,    C₂₋₆alkenyl, cyanoC₂₋₆alkenyl, —C₂₋₆alkenyl-NR²²R²³,    hydroxycarbonylC₂₋₆alkenyl, C₁₋₆alkyloxycarbonylC₂₋₆alkenyl,    C₂₋₆alkynyl, —CHO, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl,    hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³,    —CONR²²—C₁₋₆alkyl-NR²²R²³, —CONR²²—C₁₋₆alkyl-Het²,    —CONR²²—C₁₋₆alkyl-Ar², —CONR²²—O—C₁₋₆alkyl, —CONR²²—C₁₋₆alkenyl,    —NR²²R²³, —OC(O)R²⁴, —CR²⁴═NR²⁵, —CR²⁴═N—OR²⁵, —NR²⁴C(O) NR²²R²³,    —NR²⁴SO₂R²⁵, —NR²⁴C(O)R²⁵, —S(O)₀₋₂R²⁴, —SO₂NR²⁴R²⁵,    —C(NR²⁶R²⁷)═NR²⁸; —Sn(R²⁴)₃, —SiR²⁴R²⁴R²⁵, —B(OR²⁴)₂, —P(O)OR²⁴OR²⁵,    aryloxy, Het²-oxy, or a group of formula    —Z, —CO—Z or —CO—NR^(y)—Z    -    in which R^(y) is hydrogen or C₁₋₄alkyl and Z is phenyl or a 5-        or 6-membered heterocyclic ring containing one or more        heteroatoms selected from oxygen, sulphur and nitrogen, the        phenyl or heterocyclic ring being optionally substituted by one        or two substituents each independently selected from halo,        cyano, hydroxycarbonyl, aminocarbonyl, C₁₋₆alkylthio, hydroxy,        —NR²²R²³, C₁₋₆alkylsulphonylamino, C₁₋₆alkyl, haloC₁₋₆alkyl,        C₁₋₆alkyloxy or phenyl; or-   two R¹ substituents adjacent to one another on the phenyl ring may    form together a bivalent radical of formula

—O—CH₂—O— (a-1) —O—CH₂—CH₂—O— (a-2) —O—CH═CH— (a-3) —O—CH₂—CH₂— (a-4)—O—CH₂—CH₂—CH₂— (a-5) —CH═CH—CH═CH— (a-6)

-   -   R²⁴ and R²⁵ are independently hydrogen, C₁₋₆ alkyl,        —(CR₂₀R₂₁)p-C₃₋₁₀cycloalkyl or aryC₁₋₆alkyl;    -   R²⁶, R²⁷ and R²⁸ are independently hydrogen and C₁₋₆alkyl or        C(O) C₁₋₆alkyl;

-   R² is a mono- or bi-cyclic heterocyclic ring containing one or more    heteroatoms selected from oxygen, sulphur and nitrogen and    optionally substituted by one or two substituents each independently    selected from halo, cyano, hydroxy, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl,    -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³, C₁₋₆alkylsulfonylamino,    oxime, phenyl or benzyl;

-   R³ is hydrogen, halo, cyano, C₁₋₆alkyl,    —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, haloC₁₋₆alkyl, cyanoC₁₋₆alkyl,    hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, arylC₁₋₆alkyloxyC₁₋₆alkyl,    C₁₋₆alkylthioC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl,    C₁₋₆alkylcarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,    —C₁₋₆alkyl-NR²²R²³, —C₁₋₆alkyl-CONR²²R²³, arylC₁₋₆alkyl,    Het²C₁₋₆alkyl, C₂₋₆alkenyl, —C₂₋₆alkenyl, NR²²R²³, C₂₋₆alkynyl,    hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, aryl, or Het²; or a radical    of formula

—O—R¹⁰ (b-1) —S—R¹⁰ (b-2) —NR¹¹R¹² (b-3) or —N═C R^(10′)R¹¹ (b-4)wherein

-   R¹⁰ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, aryl, a    group of formula —NR²²R²³R or —C₁₋₆alkylC(O)OC₁₋₆alkyl NR²²R²³, or a    radical of formula -Alk-OR¹³ or -Alk-NR¹⁴R¹⁵;-   R^(10′) is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    arylC₁₋₆alkyl, aryl or a group of formula —NR²²R²³;-   R¹¹ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;-   R¹² is hydrogen, hydroxy, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    C₁₋₆alkylcarbonylC₁₋₆alkyl, arylC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    aryl, C₁₋₆alkyloxy, a group of formula —NR²²R²³,    C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl, haloC₁₋₆alkylcarbonyl,    arylC₁₋₆alkylcarbonyl, Het²C₁₋₆alkylcarbonyl, arylcarbonyl,    C₁₋₆alkyloxycarbonyl, trihalo C₁₋₆alkyloxycarbonyl,    C₁₋₆alkyloxyC₁₋₆alkylcarbonyl, aminocarbonyl, mono- or    di(C₁₋₆alkyl)aminocarbonyl wherein the alkyl moiety may optionally    be substituted by one or more substituents independently selected    from aryl and C₁₋₆alkyloxycarbonyl substiuents;    aminocarbonylcarbonyl, mono- or    di(C₁₋di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, or a radical of formula    -Alk-OR¹³ or Alk-NR¹⁴R¹⁵; wherein    -   Alk is C₁₋₆alkanediyl;    -   R¹³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkyl,        aryl or arylC₁₋₆alkyl;    -   R¹⁴ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or arylC₁₋₆alkyl;    -   R¹⁵ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl , C₁₋₆alkylcarbonyl, aryl or        arylC₁₋₆alkyl;-   R⁴ is a radical of formula

-   -   wherein R¹⁶ is hydrogen, halo, C₁₋₆alkyl,        —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, hydroxyC₁₋₆alkyl,        C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylS(O)₀₋₂C₁₋₆alkyl, C₁₋₆alkyloxy,        C₁₋₆alkylthio, a group of formula —NR²²R²³, hydroxycarbonyl,        C₁₋₆alkyloxycarbonyl or aryl,    -   R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aryl C₁₋₆alkyl,        trifluoromethyl, trifluoromethylC₁₋₆alkyl,        hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl, mono-        or di(C₁₋₆alkyl)aminosulphonyl or —C₁₋₆alkylP(O)OR²⁴OR²⁵;    -   R¹⁸ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl ,        arylC₁₋₆alkyl or C₁₋₆alkyloxyC₁₋₆alkyl;    -   R^(18a) is hydrogen, —SH or —SC₁₋₄alkyl;

-   R⁵ is cyano, hydroxy, halo, C₁₋₆alkyl,    —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, Het²C₁₋₆alkyloxy, hydroxycarbonyl,    C₁₋₆alkyloxycarbonyl, or a group of formula —NR²²R²³ or —CONR²²R²³;

-   R⁶ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    cyanoC₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, aminocarbonylC₁₋₆alkyl or    —C₁₋₆alkyl-NR²²R²³, R²⁴SO₂, R²⁴SO₂C₁₋₆alkyl, —C₁₋₆alkyl-OR²⁴,    —C₁₋₆alkyl-SR²⁴, —C₁₋₆alkylCONR²²—C₁₋₆alkyl-NR²²R²³,    —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Het², —C₁₋₆alkylCONR²²—C₁₋₆alkyl-Ar²,    —C₁₋₆alkyl CONR²²-Het², —C₁₋₆alkylCONR²²Ar²,    —C₁₋₆alkylCONR²²—O—C₁₋₆alkyl, —C₁₋₆alkylCONR²²—C₁₋₆alkenyl, -Alk-Ar²    or -AlkHet²;

-   R⁷ is oxygen or sulphur; or R⁶ and R⁷ together form a trivalent    radical of formula:

—CR³⁰═CR³¹—N═ (x-1) —CR³⁰═CR³¹—CR³²═ (x-6) —CR³⁰═N—N═ (x-2)—CR³⁰═N—CR³¹═ (x-7) —C(═O)—NH—N═ (x-3) —C(═O)—NH—CR³⁰═ (x-8) —N═N—N═(x-4) —N═N—CR³⁰═ (x-9) or —N═CR³⁰—N═ (x-5) —CH₂—(CH₂)⁰⁻¹—CH₂—N═ (x-10)

-   -   wherein each R³⁰, R³¹ and R³² are independently hydrogen, C₁₋₆        alkyl, —OR²⁴, —COOR²⁴, —NR²²R²³, —C₁₋₆ alkylOR²⁴, —C₁₋₆        alkylSR²⁴, R²³R²²NC₁₋₆alkyl-, —CONR²²R²³, C₂₋₆alkenyl,        C₂₋₆alkenylAr², C₂₋₆alkenylHet², cyano, amino, thio, C₁₋₆        alkylthio, —O—Ar², —S—Ar² or Ar²;    -   Ar² is phenyl, naphthyl or phenyl or naphthyl substituted by one        to five substituents each independently selected from halo,        hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³,        C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl,        aryloxy, —NR²²R²³, C₁₋₆alkylsulfonylamino, oxime or phenyl, or a        bivalent substituent of formula —O—CH₂—O— or —O—CH₂—CH₂—O—;    -   Het² is a mono- or bi-cyclic heterocyclic ring containing one or        more heteroatoms selected from oxygen, sulphur and nitrogen and        optionally substituted by one or two substituents each        independently selected from halo, hydroxy, cyano, nitro,        C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNR²²R²³, C₁₋₆alkyloxy, OCF₃,        hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, —NR²²R²³,        C₁₋₆alkylsulfonylamino, oxime or phenyl;        provided that when >Y¹—Y² is a radical of formula (y-2) or (y-4)        and (a) R⁴ is a radical of formula (c-1), (c-2) or (c-4)        and/or (b) R² is an optionally substituted imidazolyl or pyridyl        group, then R⁷ is not oxygen or sulphur.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straight and branchedchain saturated hydrocarbon radicals having from 1 to 4 carbon atomssuch as, e.g. methyl, ethyl, propyl, butyl, 1-methylethyl,2-methylpropyl and the like; C₁₋₆alkyl includes C₁₋₄alkyl and the higherhomologues thereof having 5 to 6 carbon atoms such as, for example,pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like;C₁₋₆alkanediyl defines bivalent straight and branched chained saturatedhydrocarbon radicals having from 1 to 6 carbon atoms, such as, forexample, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl,1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof;haloC₁₋₆alkyl defines C₁₋₆alkyl containing one or more halo substituentsfor example trifluoromethyl; C₂₋₆alkenyl defines straight and branchedchain hydrocarbon radicals containing one double bond and having from 2to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, and the like. The term“S(O)” refers to a sulfoxide and “S(O)₂” to a sulfone. Aryl definesphenyl, naphthalenyl or phenyl substituted with one or more substituentseach independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy ortrifluoromethyl, cyano, hydroxycarbonyl.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The compounds of formula (I) which have basic properties can beconverted in their pharmaceutically acceptable acid addition salts bytreating said base form with an appropriate acid. Appropriate acidscomprise, for example, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

The term acid addition salts also comprises the hydrates and the solventaddition forms which the compounds of formula (I) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms of compounds of formula (I), asused hereinbefore, defines all possible compounds made up of the sameatoms bonded by the same sequence of bonds but having differentthree-dimensional structures which are not interchangeable, which thecompounds of formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of a compound encompasses themixture of all possible stereochemically isomeric forms which saidcompound may possess. Said mixture may contain all diastereomers and/orenantiomers of the basic molecular structure of said compound. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto include also the pharmaceutically acceptable acid addition salts andall stereoisomeric forms.

Examples of compounds of formula (I) include those wherein one or moreof the following restrictions apply:

-   r is 0, 1 or 2;-   t is 0 or 1;-   >Y¹—Y²— is a trivalent radical of formula

>C═N— (y-1) >C═CR⁹— (y-2)

-   -   wherein R⁹ is hydrogen, cyano, halo, C₁₋₆alkyl,        hydroxyC₁₋₆alkyl, hydroxycarbonyl or aminocarbonyl;

-   R¹ is halo, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    trihalomethyl, trihalomethoxy, C₂₋₆alkenyl,    hydroxycarbonylC₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkyloxy,    hydroxyC₁₋₆alkyloxy, aminoC₁₋₆alkyloxy, C₁₋₆alkylthio,    hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, —CONR²²R²³, or —CH═NOR²⁵; or    two R¹ substituents adjacent to one another on the phenyl ring may    independently form together a bivalent radical of formula

—O—CH₂—O— (a-1) —O—CH₂—CH₂—O— (a-2)

-   R² is a 5- or 6-membered monocyclic heterocyclic ring containing    one, two or three heteroatoms selected from oxygen, sulphur or    nitrogen or a 9- or 10-membered bicyclic heterocyclic ring-   R³ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,    haloC₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,    C₁₋₆alkyloxyC₁₋₆alkyl, —C₁₋₆alkyl NR²²R²³, Het²C₁₋₆alkyl,    —C₂₋₆alkenyl NR²²R²³, or -Het²; or a group of formula

—O—R¹⁰ (b-1) —NR¹¹R¹² (b-3)

-   -   wherein R¹⁰ is hydrogen, C₁₋₆alkyl, or        —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, or a group of formula -Alk-OR¹³        or -Alk-NR¹⁴R¹⁵;    -   R¹¹ is hydrogen or C₁₋₆alkyl;    -   R¹² is hydrogen, hydroxy, C₁₋₆alkyl,        —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,        aminocarbonyl, or a radical of formula -Alk-OR¹³ or Alk-NR¹⁴R¹⁵;        -   wherein Alk is C₁₋₆alkanediyl;    -   R¹³ is hydrogen, C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;    -   R¹⁴ is hydrogen, C₁₋₆alkyl, or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;    -   R¹⁵ is hydrogen or C₁₋₆alkyl;

-   R⁴ is a radical of formula (c-2) or (c-3)    -   wherein R¹⁶ is hydrogen, halo or C₁₋₆alkyl,    -   R¹⁷ is hydrogen, C₁₋₆alkyl, —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,        C₁₋₆alkyloxyC₁₋₆alkyl or trifluoromethyl;    -   R¹⁸ is hydrogen, C₁₋₆alkyl or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl;    -   R^(18a) is hydrogen;

-   R⁵ is cyano, halo, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyloxy or    C₁₋₆alkyloxycarbonyl:

-   R⁶ is hydrogen, C₁₋₆alkyl, —C₁₋₆alkylCO₂R²⁴, —C₁₋₆alkyl-C(O)NR²²R²³,    -Alk-Ar², -AlkHet² or —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl,

-   R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of    formula (x-1), (x-2), (x-3), (x-4) or (x-9)

-   Het² is a 5- or 6-membered monocyclic heterocyclic ring containing    one, two or three heteroatoms selected from oxygen, sulphur or    nitrogen for example pyrrolidinyl, imidazolyl, triazolyl,    tetrazolyl, pyridyl, pyrimidinyl, furyl, morpholinyl, piperazinyl,    piperidinyl, thiophenyl, thiazolyl or oxazolyl, or a 9- or    10-membered bicyclic heterocyclic ring especially one in which a    benzene ring is fused to a heterocyclic ring containing one, two or    three heteroatoms selected from oxygen, sulphur or nitrogen for    example indolyl, benzofuryl, benzothienyl, quinolinyl,    benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl or    benzodioxolanyl.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   >Y¹—Y²— is a trivalent radical of formula (y-1) or (y-2), wherein R⁹    is hydrogen, halo, C₁₋₄alkyl, hydroxycarbonyl, or    C₁₋₄alkyloxycarbonyl;-   r is 0, 1 or 2;-   t is 0;-   R¹ is halo, C₁₋₆alkyl or two R¹ substituents ortho to one another on    the phenyl ring may independently form together a bivalent radical    of formula (a-1);-   R² is a 5- or 6-membered monocyclic heterocyclic ring containing one    or two heteroatoms selected from oxygen, sulphur or nitrogen or a 9-    or 10-membered bicyclic heterocyclic ring in which a benzene ring is    fused to a heterocyclic ring containing one, two or three    heteroatoms selected from oxygen, sulphur or nitrogen, optionally    substituted by halo, cyano, C₁₋₆alkyl or aryl; R³ is Het² or a group    of formula (b-1) or (b-3) wherein    -   R¹⁰ is hydrogen or a group of formula -Alk-OR¹³.    -   R¹¹ is hydrogen;    -   R¹² is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxy,        C₁₋₆alkyloxy or mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl;    -   Alk is C₁₋₆alkanediyl and R¹³ is hydrogen;-   R⁴ is a group of formula (c-2) or (c-3) wherein    -   R¹⁶ is hydrogen, halo or mono- or di(C₁₋₄alkyl)amino;    -   R¹⁷ is hydrogen or C₁₋₆alkyl;    -   R¹⁸ is hydrogen or C₁₋₆alkyl;    -   R^(18a) is hydrogen;-   R⁶ is —(CR²⁰R²¹)_(p)—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴,    aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet² or C₁₋₆alkyl;-   R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of    formula (x-1), (x-2), (x-3), (x-4) or (x-9)-   aryl is phenyl.

A particular group of compounds consists of those compounds of formula(I) wherein >Y¹—Y² is a trivalent radical of formula (y-1) or (y-2), ris 0 or 1, t is 0, R¹ is halo, C₍₁₋₄₎alkyl or forms a bivalent radicalof formula (a-1), R² is a 5- or 6-membered monocyclic heterocyclic ringcontaining one or two heteroatoms selected from oxygen, sulphur ornitrogen or a 9- or 10-membered bicyclic heterocyclic ring in which abenzene ring is fused to a heterocyclic ring containing one or twoheteroatoms selected from oxygen, sulphur or nitrogen, optionallysubstituted by halo, cyano, C₁₋₆alkyl or aryl.

R³ is hydrogen or a radical of formula (b-1) or (b-3), R¹⁰ is hydrogenor -Alk-OR¹³, R¹¹ is hydrogen and R¹² is hydrogen or

-   C₁₋₆alkylcarbonyl and R¹³ is hydrogen; R⁴ is a radical of formula    (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ is C₁₋₆alkyl, R¹⁸ is    C₁₋₆alkyl, R^(18a) is hydrogen;-   R⁶ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl, —C₁₋₆alkylCO₂R²⁴ (R²⁴═H, Et),    aminocarbonylC₁₋₆alkyl, -Alk-Ar² or -AlkHet²; and-   R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of    formula (x-2), (x-3) or (x-4).

More preferred compounds are those compounds of formula (I) wherein>Y¹—Y² is a trivalent radical of formula (y-1) or (y-2), r is 0 or 1, sis 1, t is 0, R¹ is halo, preferably chloro and most preferably3-chloro, R² is a thiophene, furyl, pyridyl, diazolyl, oxazolyl,benzodiazolyl, benzotriazolyl, or quinolinyl group, optionallysubstituted by halo preferably chloro, cyano, C₁₋₆alkyl, preferablymethyl, or aryl; R³ is hydrogen or a radical of formula (b-1) or (b-3),R⁹ is hydrogen, R¹⁰ is hydrogen, R¹¹ is hydrogen and R¹² is hydrogen; R⁴is a radical of formula (c-2) or (c-3), wherein R¹⁶ is hydrogen, R¹⁷ isC₁₋₆alkyl, R¹⁸ is C₁₋₆alkyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl,—CH₂—CH₃₋₁₀cycloalkyl or —C₁₋₆alkylAr²;

-   R⁷ is oxygen; or R⁶ and R⁷ together form a trivalent radical of    formula (x-2) or (x-4).

Especially preferred compounds are those compounds of formula (I)wherein >Y¹—Y² is a trivalent radical of formula (y-1) or (y-2), r is 1,t is 0, R¹ is halo, preferably chloro, and most preferably 3-chloro, R²is a 4-chloro-thiophen-2-yl, 3-furyl, 5-chloro-pyrid-3-yl,2-phenyl-imidazol-1-yl, 2-ethyl-imidazol-1-yl, benzimidazol-1-yl or2-hydroxy-quinoline-7-yl group; R³ is a radical of formula (b-1) or(b-3), R⁹ is hydrogen, R¹⁰ and R¹¹ are hydrogen and R¹² is hydrogen orhydroxy; R⁴ is a radical of formula (c-2) or (c-3), wherein R¹⁶ ishydrogen, R¹⁷ is C₁₋₆alkyl preferably methyl, R¹⁸ is C₁₋₆alkylpreferably methyl, R^(18a) is hydrogen; R⁶ is C₁₋₆alkyl,—CH₂—C₃₋₁₀cycloalkyl or -alkylAr²; R⁷ is oxygen; or R⁶ and R⁷ togetherform a trivalent radical of formula (x-4).

The most preferred compounds according to the invention are:

-   5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol,-   5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol,-   5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol,-   5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol,-   5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(6-quinolinyl)-tetrazolo[1,5-a]quinazoline-7-methanol,-   4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone,-   5-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol,-   5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,-   5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,-   5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine,-   α-(2-benzofuranyl)-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,-   5-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,-   4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinazolinone,-   5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(5-methyl-2-thienyl)-tetrazolo[1,5-a]quinoline-7-methanol,-   5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-tetrazolo[1,5-a]quinazoline,-   α-(2-benzofuranyl)-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine,-   5-(3-chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline,-   5-(3-chlorophenyl)-α,α-bis(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol,-   5-(3-chlorophenyl)-7-[[2-(4-fluorophenyl)-1H-imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline,-   α-benzo[b]thien-2-yl-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine,-   5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)-methyl]-tetrazolo[1,5-a]quinoline,-   5-(3-chlorophenyl)-7-[[2-(2-chlorophenyl)-1H-imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinoline,-   3-[1-[[5-(3-chlorophenyl)tetrazolo[1,5-a]quinazolin-7-yl](1-methyl-1H-imidazol-5-yl)methyl]-1H-imidazol-2-yl]-benzonitrile,-   5-(3-chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinoline,    and their pharmaceutically acceptable salts.

The compounds of formula (I) and their pharmaceutically acceptable saltsand N-oxides and stereochemically isomeric forms thereof may be preparedin conventional manner, for example by a process which comprises:

-   a) cyclising a compound of formula (II)

with a reagent serving to form a compound of formula (I) in which R⁶ ishydrogen and R⁷ is oxygen;

-   b) reacting a compound of formula (III):

in which W¹ represents a replaceable or reactive group, with a reagentserving either to react with or replace the W¹ group in compound (III)to form a compound of formula (I) in which R⁶ is hydrogen and R⁷ is anoxygen or sulphur group or to react with the W¹ group and the adjacentnitrogen atom to form directly or indirectly a compound of formula (I)in which R⁶ and R⁷ together form a trivalent radical selected fromformulae (x-1) to (x-10); or

-   c) reacting a compound of formula (IV):

in which W² is a leaving group and W³ is the group R² above or W² is thegroup R⁴ above and W³ is a leaving group, with a reagent serving toreplace the leaving group W² or W³ with the respective R⁴ or R² group;or

-   d) reacting a compound of formula (V):

(in which R^(x) is the group R² or R⁴ above) with a heterocyclic reagentof formula R^(4a)L (when R^(x) is R²) or R^(2a)L (when R^(x) is R⁴) inwhich L is a leaving atom or group and R^(2a) is R² or a precursor grouptherefor and R^(4a) is R⁴ or a precursor group therefor, and ifrequired, converting said precursor group to the parent group, to form acompound of formula (I) in which R³ is hydroxy;

-   e) reacting a compound of formula (VI):

with a reagent serving to convert the said compound (VI) to a compoundof formula (I) in which R⁶ is hydrogen and R⁷ is oxygen;and optionally effecting one or more of the following conversions in anydesired order:

-   -   (i) converting a compound of formula (I) into a different        compound of formula (I);    -   (ii) converting a compound of formula (I) in to a        pharmaceutically acceptable salt or N-oxide thereof;    -   (iii) converting a pharmaceutically acceptable salt or N-oxide        of a compound of formula (I) into the parent compound of formula        (I);    -   (iv) preparing a stereochemical isomeric form of a compound of        formula (I) or a pharmaceutically acceptable salt or N-oxide        thereof.

With regard to process a), this can be effected as described for examplein an analogous manner to that described in WO 97/21701 and WO98/49157referred to above. Thus, the cyclisation may be effected for example bysubjecting the compound of formula (II) to an acetylation reaction, e.g.by treatment with the anhydride of a carboxylic acid, e.g. aceticanhydride in a reaction-inert solvent, e.g. toluene, and subsequentreaction with a base such as potassium tert-butoxide in a reaction-inertsolvent such as 1,2-dimethoxyethane.

With regard to process b), this can also be effected for example in ananalogous manner to that as described in WO 97/21701 and WO98/49157referred to above for the preparation of compounds in which R⁷ isoxygen, for example by hydrolysis of an ether of formula (III) in whichW¹ is C₁₋₆alkyloxy in an aqueous acid solution such hydrochloric acid.Alternatively a compound of formula (III) in which W¹ is a chlororadical can be used.

Also with regard to process b), for the preparation of compounds inwhich R⁶ and R⁷ together form a trivalent radical of formula (x-1) to(x-10), this can be effected as described for example in WO 00/39082referred to above. For example, when W¹ is chloro, the compound offormula (III) can be reacted with an azide compound for example sodiumazide to form a corresponding compound of formula (I) in which R⁶ and R⁷together form a trivalent radical of formula (x-4). Alternatively, whenW¹ is chloro, the compound of formula (III) can be reacted with aquoushydrazine to form a compound of formula (III) where W¹ is NHNH₂ which byreaction with sodium nitrite in acidic media form a correspondingcompound of formula (I) in which R⁶ and R⁷ together form a trivalentradical of formula (x-4).

With regard to process c), this can be effected for example byN-alkylating an intermediate of formula (IVa), wherein W² is anappropriate leaving group such as, for example, chloro, bromo,methanesulfonyloxy or benzenesulfonyloxy, with an intermediate offormula (VII) to form a a compound of formula (I) in which R⁴ is a groupof formula (c-1) represented by compounds of formula (I-a):

The reaction can be performed in a reaction-inert solvent such as, forexample, acetonitrile, and optionally in the presence of a suitable basesuch as, for example, sodium carbonate, potassium carbonate ortriethylamine. Stirring may enhance the rate of the reaction. Thereaction may conveniently be carried out at a temperature rangingbetween room temperature and reflux temperature.

Also, compounds of formula (I-a) can be prepared by reacting anintermediate of formula (IVb) in which W² is hydroxy with anintermediate of formula (VIII), wherein Y is oxygen or sulfur, such as,for example, a 1,1′-carbonyldiimidazole.

Said reaction may conveniently be conducted in a reaction-inert solvent,such as, e.g. tetrahydrofuran, optionally in the presence of a base,such as sodium hydride, and at a temperature ranging between roomtemperature and the reflux temperature of the reaction mixture.

Similar procedures can be used to introduce the R² group using acompound of formula (IV) in which W³ is a leaving group.

With regard to process d), this can be used to introduce the R⁴ group,for example by reacting a compound of formula (V) in which R^(x) is R²with an imidazole reagent to form a compound of formula (I) in which R⁴is a group of formula (c-2), or with a3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole reagent to form the corresponding3-mercapto-4-C₁₋₆alkyl-1,2,4-triazole derivative, which is optionallymethylated to form the corresponding 3-methylmercapto derivative, andsubsequently removing the 3-mercapto or 3-methylmercapto group to form acompound of formula(I) in which R⁴ is a group of formula (c-3) in whichR¹⁸ is a C₁₋₆alkyl group; or with a 3-bromopyridyl group to form acompound of formula (I) in which R⁴ is a group of formula (c-4). In moredetail, the compounds of formula (I) wherein R⁴ represents a radical offormula (c-2), R³ is hydroxy and R¹⁷ is C₁₋₆alkyl, said compounds beingreferred to as compounds of formula (I-b-1) may be prepared by reactingan intermediate ketone of formula (Va) with an intermediate of formula(III-1). Said reaction requires the presence of a suitable strong base,such as, for example, butyl lithium in an appropriate solvent, such as,for example, tetrahydrofuran, and the presence of an appropriate silanederivative, such as, for example, triethylchlorosilane. During thework-up procedure an intermediate silane derivative is hydrolyzed. Otherprocedures with protective groups analogous to silane derivatives canalso be applied.

Also, the compounds of formula (I), wherein R⁴ is a radical of formula(c-2), R³ is hydroxy and R¹⁷ is hydrogen, said compounds being referredto as compounds of formula (I-b-2) may be prepared by reacting anintermediate ketone of formula (Va) with a intermediate of formula(III-2), wherein PG is a protective group such as, for example, asulfonyl group, e.g. a dimethylamino sulfonyl group, which can beremoved after the addition reaction. Said reaction is conductedanalogously as for the preparation of compounds of formula (I-b-1),followed by removal of the protecting group PG, yielding compounds offormula (I-b-2). Similar procedures can be used to introduce the R²group by reacting a compound of formula (V) in which R^(x) is R⁴ with aR²L reagent for example a lithium compound.

With regard to process e), this may be effected for example as describedin WO 97/21701 referred to above, by reacting the nitrone of formula(VI) with the anhydride of a carboxylic acid, e.g. acetic anhydride,thus forming the corresponding ester on the 2-position of the quinolinemoiety, which ester can then be hydrolysed in situ to the correspondingquinolinone using a base such potassium carbonate.

Examples of the interconversion of one compound of formula (I) into adifferent compound of formula (I) include the following reactions:

-   a) compounds of formula (I-b) can be converted to compounds of    formula (I-c), defined as a compound of formula (I) wherein R⁴ is a    radical of formula (c-2) and R³ is hydrogen, by submitting the    compounds of formula (I-b) to appropriate reducing conditions, such    as, e.g. stirring in acetic acid in the presence of formamide, or    treatment with sodium borohydride/trifluoroacetic acid.

-   b) compounds of formula (I-b) can be converted to compounds of    formula (I-f) wherein R³ is halo, by reacting the compounds of    formula (I-b) with a suitable halogenating agent, such as, e.g.    thionyl chloride or phosphorus tribromide. Successively, the    compounds of formula (I-f) can be treated with a reagent of formula    H—NR¹¹R¹² in a reaction-inert solvent, thereby yielding compounds of    formula (I-g).

-   c) compounds of formula (I-b) can be converted into compounds of    formula (I-g) for example by treatment with SOCl₂, and then    NH₃/iPrOH, e.g. in a tetrahydrofuran solvent, or by treatment with    acetic acid ammonium salt at a temperature ranging from 120 to 180°    C., or by treatment with sulfamide at a temperature ranging from 120    to 180° C.;-   d) compounds of formula (I-f) can be converted into compounds of    formula (I-c) for example by treatment with SnCI₂ in the presence of    concentrated HCl in acetic acid at reflux;-   e) compounds of formula (I) in which >Y¹—Y² represents a radical of    formula (y-1) or (y-2) can be convened into corresponding compounds    of formula (I) in which >Y¹—Y² represents a radical of formula (y-3)    or (y-4) respectively, by conventional reduction procedures for    example hydrogenation or reduction by treatment with sodium    borohydride in a suitable solvent, e.g. methanol, and vice versa by    conventional oxidation procedures, e.g. oxidation with MnO₂ in a    reaction-inert solvent, e.g. dichloromethane;-   f) compounds of formula (I) in which X is oxygen can be converted    into corresponding compounds of formula (I) in which X is sulphur    with a reagent such as phosphorus pentasulfide or Lawesson's reagent    in a suitable solvent such as, for example, pyridine.

The compounds of formula (I) may also be converted into each other viaart-known reactions or functional group transformations. A number ofsuch transformations are already described hereinabove. Other examplesare hydrolysis of carboxylic esters to the corresponding carboxylic acidor alcohol; hydrolysis of amides to the corresponding carboxylic acidsor amines; hydrolysis of nitriles to the corresponding amides; aminogroups on imidazole or phenyl may be replaced by a hydrogen by art-knowndiazotation reactions and subsequent replacement of the diazo-group byhydrogen; alcohols may be converted into esters and ethers; primaryamines may be converted into secondary or tertiary amines; double bondsmay be hydrogenated to the corresponding single bond.

The intermediates and starting materials used in the above-describedprocesses may be prepared in conventional manner using procedures knownin the art for example as described in the above-mentioned patentspecifications WO 97/16443, WO 97/21701, WO 98/40383, WO 98/49157 and WO00/39082.

Compounds of formula (III) in which W¹ is chloro, R³ is hydroxy andY¹—Y² is (y-1), herein referred to as compounds of formula (IIIa), maybe prepared for example by procedures summarised in the followingsynthetic Routes A, B, C and D:

Compounds of formula (III) in which W¹ is chloro, R³ is hydroxy andY¹—Y² is (y-2), herein referred to as compounds of formula (IIIb), maybe prepared for example by procedures summarised in the followingsynthetic Routes E and F:

Compounds of formula (IV) in which W³ is chloro, R³ is hydrogen, Y¹—Y²is (y-2) and R⁶ and R⁷ are (x-4), herein referred to as compounds offormula (IVa), may be prepared for example by procedures summarised inthe following synthetic Routes G and H:

Compounds of formula (IV) in which W³ is chloro, R³ is hydrogen, Y¹—Y²is (y-1), R⁶ and R⁷ are (x-4), herein referred to as compounds offormula (IVb) may be prepared for example by procedures summarised inthe following synthetic Route I:

Compounds of formula (V) can be prepared in an analogous manner to theprocedures described above for the preparation of other startingmaterials. For example certain of such compounds of formula (V) areprepared in the above described routes, for example compounds of formula(V) in which Y¹—Y² is (y-1), R⁶ is hydrogen and R⁷ is oxygen and R^(x)is R² correspond to compounds of formula (XIV) in Route A, and compoundsof formula (V) in which Y¹—Y² is (y-2) and R⁶ and R⁷ are (x-4) andcorrespond to compounds of formula (XXXVIII) in Route H.

The compounds of formula (I) and some of the intermediates have at leastone stereogenic center in their structure. This stereogenic center maybe present in a R or a S configuration.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of the invention. Abnormal growth of cells refers to cellgrowth independent of normal is regulatory mechanisms (e.g. loss ofcontact inhibition). This includes the abnormal growth of: (1) tumorcells (tumors) expressing an activated ras oncogene; (2) tumor cells inwhich the rat protein is activated as a result of oncogenic mutation ofanother gene; (3) benign and malignant cells of other proliferativediseases in which aberrant ras activation occurs. Furthermore, it hasbeen suggested in literature that ras oncogenes not only contribute tothe growth of tumors in vivo by a direct effect on tumor cell growth butalso indirectly, i.e. by facilitating tumor-induced angiogenesis (Rak.J. et al, Cancer Research, 55, 4575–4580, 1995). Hence,pharmacologically targeting mutant ras oncogenes could conceivablysuppress solid tumor growth in vivo, in part, by inhibitingtumor-induced angiogenesis.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of the compound of the invention to asubject, e.g. a mammal (and more particularly a human) in need of suchtreatment. In particular, this invention provides a method forinhibiting the growth of tumors expressing an activated ras oncogene bythe administration of an effective amount of the compound of theinvention. Examples of tumors which may be inhibited, but are notlimited to, lung cancer (e.g. adenocarcinoma and including non-smallcell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma suchas, for example exocrine pancreatic carcinoma), colon cancers (e.g.colorectal carcinomas, such as, for example, colon adenocarcinoma andcolon adenoma), hematopoietic tumors of lymphoid lineage (e.g. acutelymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloidleukemias (for example, acute myclogenous leukemia (AML)), thyroidfollicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymalorigin (e.g. fibrosarcomas and rhabdomyosarcomas), melanomas,teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin(e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer),kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermalcarcinoma.

This invention may also provide a method for inhibiting proliferativediseases, both benign and malignant, wherein ras proteins are aberrantlyactivated as a result of oncogenic mutation in genes. With saidinhibition being accomplished by the administration of an effectiveamount of the compounds described herein, to a subject in need of such atreatment. For example, the benign proliferative disorderneurofibromatosis, or tumors in which ras is activated due to mutationor overexpression of tyrosine kinase oncogenes, may be inhibited by thecompounds of this invention.

The compound according to the invention can be used for othertherapeutic purposes, for example:

-   -   a) the sensitisation of tumors to radiotherapy by administering        the compound according to the invention before, during or after        irradiation of the tumor for treating cancer, for example as        described in WO 00/01411;    -   b) treating athropathies such as rheumatoid arthritis,        osteoarthritis, juvenile arthritis, gout, polyarthritis,        psoriatic arthritis, ankylosing spondylitis and systemic lupus        erythematosus, for example as described in WO 00/1386;    -   c) inhibiting smooth muscle cell proliferation including        vascular proliferative disorders, atherosclerosis and        restenosis, for example as described in WO 98/55124;    -   d) treating inflammatory conditions such as ulcerative colitis,        crohn's disease, allergic rhinitis, graft vs host disease,        conjunctivitis, asthma, ards, behcets disease, transplant        rejection, uticaria, allergic dermatitis, alopecia areata,        scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes,        systemic lupus erythematosis, kawasaki's disease, multiple        sclerosis, emphysema, cystic fibrosis and chronic bronchitis;    -   e) treating endometriosis, uterine fibroids, dysfunctional        uterine bleeding and endometrial hyperplasia;    -   f) treating ocular vascularisation including vasculopathy        affecting retinal and choroidal vessels;    -   g) treating pathologies resulting from heterotrimeric G protein        membrane fixation including diseases related to following        biological functions or disorders; smell, taste, light,        perception, neurotransmission, neurodegeneration, endocrine and        exocrine gland functioning, autocrine and paracrine regulation,        blood pressure, embryogenesis, viral infections, immunological        functions, diabetes, obesity;    -   h) inhibiting viral morphogenesis for example by inhibiting the        prenylation or the post-prenylation reactions of a viral protein        such as the large delta antigen of hepatitis D virus; and the        treatment of HIV infections;    -   i) treating polycystic kidney disease;    -   j) suppressing induction of inducible nitric oxide including        nitric oxide or cytokine mediated disorders, septic shock,        inhibiting apoptosis and inhibiting nitric oxide cytotoxicity;    -   k) treating malaria.

The compounds of present invention are particularly useful for thetreatment of proliferative diseases, both benign and malignant, whereinthe K-ras B isoform is activated as a result of oncogenic mutation.

Hence, the present invention discloses the compounds of formula (I) foruse as a medicine as well as the use of these compounds of formula (I)for the manufacture of a medicament for treating one or more of theabove-mentioned conditions.

For the treatment of the above conditions, the compound of the inventionmay be advantageously employed in combination with one or more otheranti-cancer agents for example selected from platinum coordinationcompounds for example cisplatin or carboplatin, taxane compounds forexample paclitaxel or docetaxel, camptothecin compounds for exampleirinotecan or topotecan, anti-tumor vinca alkaloids for examplevinblastine, vincristine or vinorelbine, anti-tumor nucleosidederivatives for example 5-fluorouracil, gemcitabine or capecitabine,nitrogen mustard or nitrosourea alkylating agents for examplecyclophosphamide, chlorambucil, carmustine or lomustine, anti-tumoranthracycline derivatives for example daunorubicin, doxorubicin oridarubicin; HER2 antibodies for example trastzumab; and anti-tumorpodophyllotoxin derivatives for example etoposide or teniposide; andantiestrogen agents including estrogen receptor antagonists or selectiveestrogen receptor modulators preferably tamoxifen, or alternativelytoremifene, droloxifene, faslodex and raloxifene, or aromataseinhibitors such as exemestane, anastrozole, letrazole and vorozole.

For the treatment of cancer the compounds according to the presentinvention can administered to a patient as described above inconjunction with irradiation; such treatment as may be especiallybeneficial as farnesyl transferase inhibitors can act asradiosensitisers for example as described in International PatentSpecification WO 00/01411, enhancing the therapeutic effect of suchirradiation.

Irradiation means ionizing radiation and in particular gamma radiation,especially that emitted by linear accelerators or by radionuclides thatare in common use today. The irradiation of the tumor by radionuclidescan be external or internal.

Preferably, the administration of the farnesyl transferase inhibitorcommences up to one month, in particular up to 10 days or a week, beforethe tumor. Additionally, it is advantageous to fractionate theirradiation of the tumor and maintain the administration of the farnesyltransferase inhibitor in the interval between the first and the lastirradiation session.

The amount of farnesyl protein transferase inhibitor, the dose ofimdiation and the intermittence of the irradiation doses will depend ona series of parameters such as the type of tumor, its location, thepatients' reaction to chemo- or radiotherapy and ultimately is for thephysician and radiologists to determine in each individual case.

The present invention also concerns a method of cancer therapy for ahost harboring a tumor comprising the steps of

-   -   administering a radiation-sensitizing effective amount of a        farnesyl protein transferase inhibitor according to the        invention before, during or after    -   administering radiation to said host in the proximity to the        tumor.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical fornn foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a particular compound, in base or acid addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin Said additives may facilitate the administration to the skin and/ormay be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the pharmaceutical carrier.Examples of such dosage unit forms are tablets (including scored orcoated tablets), capsules, pills, powder packets, wafers, injectablesolutions or suspensions, teaspoonfuls, tablespoonfuls and the like, andsegregated multiples thereof.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that an effective amount would be from 0.01 mg/kg to 100mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg bodyweight. It may be appropriate to administer the required dose as two,three, four or more sub-doses at appropriate intervals throughout theday. Said sub-doses may he formulated as unit dosage forms, for example,containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of activeingredient per unit dosage form.

The following examples are provided for purposes of illustration.

Experimental Part

Hereinafter “THF” means tetrahydrofuran, “DIPE” meane diisopropylether,“DMF” means N,N-dimethylformamide, “EtOAc” means ethyl acetate, “BTEAC”means benzyltriethylammonium chloride and “BuLi” means n-butyl lithium.

A. PREPARATION OF THE INTERMEDIATES EXAMPLE A1

-   a) NaOH (0.62 mol) was dissolved in methanol (100 m) and the mixture    was cooled till room temperature. 1-Bromo-4-nitro-benzene (0.124    mol), followed by 3-chlorobenzeneacetonitrile (0.223 mol) were added    dropwise, the temperature raised till 50° C. and the mixture was    stirred at room temperature overnight. The mixture was poured into    water and ice, the precipitate was filtered off, washed with water    and extracted with CH₂Cl₂ and CH₃OH. The organic layer was dried    (MgSO₄), filtered off and evaporated till dryness. The residue was    taken up in diethyl ether, filtered off and dried, yielding 13.2 g    (34.8%) of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxasole    (intermediate 1), melting point: 163° C.-   b) BuLi (0.0021 mol) was added dropwise at −70° C. to solution of    intermediate 1 (0.0016 mol) in THF (5 ml). The mixture was stirred    at −70° C. for 15 minutes. A solution of    2-thiophenecarboxaldehyde-5-chloro- (0.0019 mol) in THF (3 ml) was    added dropwise. The mixture was stirred at −70° C. for 1 hour,    poured out into ice water and extracted with CH₂Cl₂. The organic    layer was separated, dried (MgSO₄), filtered, and the solvent was    evaporated. This product was used without further purification,    yielding    3-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-2,1-benzisoxazole-5-methanol    (intermediate 2).-   c) MnO₂ (0.6 g) was added to a mixture of intermediate 2 (0.0016    mol) in dioxane (6 ml). The mixture was stirred and refluxed for 6    hours, then cooled and filtered over celite. The solvent was    evaporated. The residue was crystallized from 2-propanone. The    precipitate was filtered off and dried. The precipitate (0.6 g) was    purified by column chromatography over silica gel (eluent:    CH₂Cl₂/cyclohexane; 80/20 to 100; 15–35 μm). The fractions were    collected and the solvent was evaporated. Yielding: 0.3 g (49%) of    [3-(3-chlorophenyl)2,1-benzisoxazol-5-yl](5-chloro-2-thienyl)-methanone    (intermediate 3), melting point: 176° C.-   d) TiCl₃ 15% in water (130 ml) was added dropwise to a solution of    intermediate 3 (0.0347 mol) in THF (130 ml). The mixture was stirred    at room temperature overnight. TiCl₃ 15% in water (50 ml) was added.    The mixture was stirred for a week-end, poured out into ice water,    extracted with CH₂Cl₂, basified with K₂CO₃ 10%, extracted and washed    with water. The organic layer was separated, dried (MgSO₄),    filtered, and the solvent was evaporated, yielding 13 g (100%) of    [4-amino-3-[1-(3-chlorobenzoyl)]phenyl](5-chloro-2-thienyl)-methanone    (intermediate 4).-   e) Trichloro-acetyl chloride, (0.0416 mol) then triethylamine    (0.0416 mol) were added dropwise at 5° C. to a solution of    intermediate 4 (0.0347 mol) in CH₂Cl₂ (130 ml) under N₂ flow. The    mixture was stirred at room temperature overnight, poured out into    water and extracted with CH₂Cl₂. The organic layer was separated,    dried (MgSO₄), filtered, and the solvent was evaporated, yielding    (100%) of    2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-[(5-chloro-2-thienyl)carbonyl]phenyl]-acetamide    (intermediate 5).-   f) Ammonium acetate (0.0694 mol) was added to a solution of    intermediate 5 (0.0347 mol) in dimethylsulfoxide (180 ml). The    mixture was stirred at 60° C. for 4 hours, then cooled and poured    out into ice water. The precipitate was filtered, taken up in CH₃CN    (warm), filtered, washed CH₃CN and diethyl ether and dried under a    vacuum, yielding 11.67 g (83.8%) of    4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)carbonyl]-2(1H)-quinazolinone    (intermediate 6).-   g) A mixture of intermediate 6 (0.0279 mol) in phosphoryl chloride    (70 ml) was stirred at 100° C. for 2 hours and cooled. The solvent    was evaporated. The residue was taken up in CH₂Cl₂. The solvent was    evaporated. The residue was taken up in CH₂Cl₂, poured out into ice    water, basified with K₂CO₃, extracted with CH₂Cl₂ and was washed    with water. The organic layer was separated, dried (MgSO₄), filtered    and the solvent was evaporated. The residue was crystallized from    CH₃CN. The precipitate was filtered off and dried. Yielding: 10.35 g    (88.4%) of    [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](5-chloro-2-thienyl)-methanone    (intermediate 7). The mother layer was evaporated. The residue was    purified by colucolumn chromatography over silica gel (eluent:    cyclohexane/EtOAc 90/10; 15–40 μm). The pure fractions were    collected and the solvent was evaporated, yielding 0.4 g (3.4%) of    [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](5-chloro-2-thienyl)-methanone    (intermediate 7), melting point: 186 ° C.-   h) BuLi (0.0404 mol) was added dropwise at −70° C. to a solution of    1-methyl-1H-imidazole (0.023 mol) in THF (40 ml) under N₂ flow. The    mixture was stirred for 15 minutes. Chlorotriethyl-silane (0.0414    mol) was added dropwise. The mixture was stirred at −70° C. for 15    minutes. nBuLi (0.0356 mol) was added dropwise. The mixture was    stirred for 15 minutes. A solution of intermediate 7 (0.023 mol) in    THF (100 ml) was added at −70° C. The mixture was stirred at −70° C.    for 1 hour, poured out in to water, extracted with CH₂Cl₂ and washed    with water. The organic layer was separated, dried (MgSO₄),    filtered, and the solvent was evaporated. The residue was purified    by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH    96/4/0.2; 15–40 μm). The fractions were collected and the solvent    was evaporated. Yielding: 2.75 g (24%) of    2-chloro-4-(3-chloropbenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol    (intermediate 8).

EXAMPLE A2

-   a) TiCl₃ 15% in water (1050 ml) was added at room temperature to a    solution of (intermediate 1) (0.386 mol) in THF (1350 ml) and the    mixture was stirred at room temperature for 2 h. The mixture was    poured into water and ice and extracted with CH₂Cl₂. The organic    layer was decanted, washed with K₂CO₃ 10%, dried (MgSO₄), filtered    off and evaporated, yielding 102 g (85%) of(2-amino-5-bromophenyl)    (3-chlorophenyl)-methanone (intermediate 9).-   b) A solution of intermediate 9 (0.328 mol) and acetic acid    anhydride (0.656 mol) in toluene (1200 ml) was stirred and refluxed    for one night. The mixture was evaporated and the product was used    without further purification, yielding 139 g (quant.) of    N-[4-bromo-2-(3-chlorobenzoyl)phenyl]-acetamide (intermediate 10).-   c) 2-methyl-2-propanol, potassium salt (1.635 mol) was added    portionwise at room temperature to a solution of intermediate 10    (0.328 mol) in 1,2-dimethoxyethane (1200 ml) and the mixture was    stirred at room temperature for one night. The mixture was    evaporated till dryness, the residue was poured into water and ice    and decanted. The oily residue was taken up in DIPE, the precipitate    was filtered off, washed with EtOAc, CH₃CN and diethyl ether and    dried, yielding 88.6 g (80.76%) of    6-brome-4-(3-chlorophenyl)-2(1H)-quinolinone (intermediate 11).-   d) A mixture of intermediated 11 (0.16 mol) in phosphoryl chloride    (500 ml) was stirred and refluxed for one night. The mixture was    evaporated till dryness, the residue was taken up in ice and water,    alkalized with NH₄OH and extracted with CH₂Cl₂. The organic layer    was decanted, dried (MgSO₄), filtered off and evaporated, yielding    56 g (100%) of 6-bromo-2-chloro-4-(3-chlorophenyl)quinoline    (intermediate 12).-   e) CH₃ONa 30%/CH₃OH (96 ml) was added to a solution of intermediate    12 (0.16 mol) in methanol (500 ml) and the mixture was stirred and    refluxed for one night. The mixture was evaporated till dryness, the    residue was taken up in CH₂Cl₂, washed with water and decanted. The    organic layer was dried (MgSO₄); filtered off and evaporated. The    residue was taken up in diethyl ether and DIPE, the precipitate was    filtered off and dried, yielding 48 g (86%) of    6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (intermediate 13).-   f) Intermediate 13 (0.0287 mol) was dissolved in THF (100 ml) under    N₂ flow. The mixture was cooled to −20° C. and then BuLi 1.6M in    hexane was added dropwise. The mixture stood at −30° C. for 30 min.,    and then DMF (0.0574 mol) was added. The mixture was allowed to warm    to room temperature, hydrolyzed and extracted with EtOAc. The    organic layer was decanted, dried (MgSO₄), filtered, and the solvent    was evaporated. The residue (10 g) was purified by column    chromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 60/40;    15–40 μm). The pure fractions were collected and the solvent was    evaporated, yielding 7.5 g (88%) of    4-(3-chlorophenyl)-2-methoxy-6-quinolinecarboxaldehyde (intermediate    14).-   g) A mixture of N-(1-methylethyl)-2-propanamine (0.0891 mol) in    diethyl ether (270 mol) was cooled to −70° C. BuLi 1.6 M in hexane    (0.0891 mol) was added dropwise. The mixture was stirred at −70° C.    for 2 min. 2-Chloro-thiophene (0.104 mol) was added. The mixture was    stirred at −70° C. for 30 min. A solution of intermediate 14 (0.0742    mol) in THF (110 ml) was added dropwise. The mixture was stirred at    −70° C. for 1 hour, brought to −30° C., hydrolyzed and extracted    with EtOAc. The organic layer was separated, dried (MgSO₄), filtered    and the solvent was evaporated till dryness. The residue (31.5 g)    was purified by column chromatography over silica gel (eluent:    cyclohexane/EtOAc 80/20; 20–45 μm). Two pure fractions were    collected and their solvents were evaporated, yielding 21.7 g (70%)    of    4-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-2-methoxy-6-quinolinemethanol    (intermediate 15).-   h) A mixture of intermediate 15 (0.0521 mol) and MnO₂ (20 g) in    trichloromethane (200 ml) was stirred and refluxed for several    hours. The mixture was filtered over celite and the solvent was    evaporated till dryness, yielding 21.7 g (100%) of    [4-(3-chlorophenyl)-2-methoxy-6-quinolinyl](5-chloro-2-thienyl)-methanone    (intermediate 16).-   i) A mixture of intermediate 16 (0.0521 mol) in HCl 3N (200 ml) and    THF (200 ml) was stirred and refluxed for 48 hours and then poured    out on ice. The precipitate was filtered off, washed with diethyl    ether and dried, yielding 19.1 g (92%) of    4-(3-chlorophenyl)-6-[(5-2-thienyl)carbonyl]-2(1H)-quinolinone    (intermediate 17), melting point: 260° C.-   j) A mixture of intermediate 17 (0.0477 mol), iodomethane (0.0954    mol) and BTEAC (0.0239 mol) in THF (200 ml) and concentrated NaOH    (200 ml) was stirred vigorously at room temperature for 1 hour.    Water was added and the mixture was extracted with CH₂Cl₂ and CH₃OH.    The organic layer was separated, dried (MgSO₄), filtered and the    solvent was evaporated till dryness. The residue (32.3 g) was    purified by column chromatography over silica gel (eluent    CH₂Cl₂/EtOAc 85/15; 20–45 μm). The pure fractions were collected and    the solvent was evaporated. The residue was taken up in diethyl    ether. The precipitate was filtered off, washed with 2-propanone and    diethyl ether and dried, yielding 18 g (91%) of    4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)carbonyl]-1-methyl-2(1H)-quinolinone    (intermediate 18), melting point: 178° C.-   k) BuLi (0.00472 mol) was added dropwise at −70° C. to a solution of    2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.00229 mol) in THF    (6 ml) under N₂ flow. The mixture was stirred at −70° C. for 1 hour,    then brought to 0° C., stirred at 0° C. for 1 hour and cooled to    −70° C. Intermediate 18 (0.00121 mol) was added portionwise at    −70° C. The mixture was stirred at −70° C. for 1 hour, brought    slowly to 0° C., stirred at 0° C. for 1 hour and poured out into    water. EtOAc was added. The mixture was extracted with EtOAc. The    organic layer was washed with water, separated, dried (MgSO₄),    filtered, and the solvent was evaporated. The residue was purified    by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH    90/10/1; 15–40 μm). The pure fractions were collected and the    solvent was evaporated. The residue (0.17 g, 27%) was washed with    diethyl ether, filtered and dried under a vacuum, yielding 0.13 g    (20%) of    4-(3-chloropbenyl)-6-[(5-chloro-2-thienyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone    (intermediate 19).

EXAMPLE A3

-   a) BuLi 1.6M in hexane (0.0156 mol) was added dropwise at −70° C. to    a mixture of 6-bromo-2-chloro-4(3-chlorophenyl)quinoline (0.0142    mol) in THF (70 ml) under N₂ flow. The mixture was stirred at    −70° C. for 30 minutes. A solution of 3-furancarboxaldebyde (0.0212    mol) in THF (5 ml) was added dropwise. The mixture was stirred from    −70° C. to room temperature for 2 hours. Water was added. The    mixture was extracted with EtOAc. The organic layer was separated,    dried (MgSO₄), filtered and the solvent was evaporated. The residue    (5.8 g) was purified by column chromatography over silica gel    (eluent: cyclobexane/EtOAc 70/30; 15–40 μm). The pure fractions were    collected and the solvent was evaporated, yielding 3 g (57%) of    2-chloro-4-(3-chlorophenyl)-α-(3furanyl)-6-quinolinemethanol    (intermediate 20), melting point: 162° C.-   b) A mixture of intermediate 20 (0.0076 mol) and MnO₂ (0.03 mol) in    dioxane (30 ml) was stirred and refluxed for 48 hours, cooled and    filtered over celite. Celite was rinsed with CH₂Cl2. The solvent was    evaporated. The residue was crystallized from 2-propanone/diethyl    ether. The precipitate was filtered off and dried, yielding 0.93 g    (33%) of    [2-chloro-4-(3-chloropbenyl)-6-quinolinyl]-3-furanyl-methanone    (intermediate 21), melting point 152° C.-   c) BuLi (0.0109 mol) was added dropwise at −70° C. to a solution of    1-methyl-1H -imidazole (0.0109 mol) in THF (13 ml) under N₂ flow.    The mixture was stirred at −70° C. for 15 minutes.    Chlorotriethyl-sllane (0.0112 mol) was added dropwise. The mixture    was stirred at −70° C. for 15 minutes. BuLl (0.0097 mol) was added    dropwise. The mixture was stirred at −70° C. for 15 minutes. A    solution of intermediate 21 (0.0062 mol) in THF (12 ml) was added at    −70° C. The mixture was stirred at −70° C. for 30 minutes. Water was    added. The mixture was extracted with EtOAc. The organic layer was    separated, dried (MgSO₄), filtered, and the solvent was evaporated.    The residue (4.2 g) was purified by column chromatography over    silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 15–40 μm). The    fractions were collected and the solvent was evaporated. Yielding:    1.15 g 41%). A sample (0.6 g) was crystallized from 2-propanone. The    precipitate was filtered off and dried, yielding 0.51 g of    2-chloro-4-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinolinemethanol    (intermediate 22), melting point: 246° C.

EXAMPLE A4

-   a) BuLi (0.13 mol) was added dropwise at −78° C. to a solution of    5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.113 mol) in THF    (350 ml) under N₂ flow. The mixture was stirred at −70° C. for 15    minutes. A solution of 6-quinolinecarboxaldehyde (0.124 mol) in THF    (200 ml) was added dropwise. The mixture was stirred at −78° C. for    1 hour, poured out into water and extracted with CH₂Cl₂. The organic    layer was separated, dried (MgSO₄), filtered, and the solvent was    evaporated. The residue was purified by column chromatography over    silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 to 98/2 to 0/100; 75–200 μm).    Two fractions were collected and the solvent was evaporated,    yielding 7 g of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole    (starting material) and 31 g (70.9%) of    α-[3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl]-6-quinolinemethanol    (intermediate 23).-   b) MnO₂ (31 g) was added to a solution of intermediate 23 (0.08 mol)    in dioxane (300 ml). The mixture was stirred and refluxed for 4    hours, cooled and filtered over celite. The solvent was evaporated.    The residue was washed with 2-propanone, filtered off and dried,    yielding 19.5 g (63.3%) of    [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl]-6-quinolinyl-methanone    (intermediate 24).-   c) TiCl₃ 15% in water (20 ml) was added dropwise to a solution of    intermediate 24 (0.0052 mol) in THF (20 ml). The mixture was stirred    at room temperature overnight, poured out into ice water, extracted    with CH₂Cl₂ and basified with K₂CO₃ 10%. The organic layer was    separated, dried (MgSO₄), filtered, and the solvent was evaporated,    yielding 2 g (100%) of    [4-amino-3-[1-(3-chlorobenzoyl)]phenyl]-6-quinolinyl-methanone    (intermediate 25).-   d) Trichloro-acetyl chloride (0.0062 mol) then triethylamine (0.0062    mol) were added at 5° C. to a solution of intermediate 25 (0.00517    mol) in CH₂Cl₂ (20 ml) under N₂ flow. The mixture was brought to    room temperature, stirred at room temperature for 3 hours, poured    out into ice water and extracted with CH₂Cl₂. The organic layer was    separated, dried (MgSO₄), filtered, and the solvent was evaporated,    yielding 2.62 g (95%) of    2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-(6-quinolinylcarbonyl)phenyl]-acetamide    (intermediate 26).-   e) A mixture of intermediate 26 (0.00492 mol) and ammonium acetate    (0.00984 mol) in dimethylsulfoxide (25 ml) was stirred at 60° C. for    4 hours and poured out into ice water. The precipitate was filtered,    taken up in acetonitrile (warm) and water, filtered and dried under    a vacuum. A part (0.5 g) of this fraction (1 g, 49%) was purified by    column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH    95/5/0.1; 15–40 μm). The pure fractions were collected and the    solvent was evaporated, yielding 0.2 g of    4-(3-chlorophenyl)-6-(6-quinolinylcarbonyl)-2(1H)-quinazolinone    (intermediate 27), melting point: >260° C.-   f) A mixture of intermediate 27 (0.0325 mol) in phosphoryl chloride    (80 ml) was stirred at 100° C. for 2 hours, then cooled and the    solvent was evaporated. The residue was taken up in CH₂Cl₂, poured    out into ice water, basified with K₂CO₃ 10% and extracted with    CH₂Cl₂. The organic layer was washed with water, dried (MgSO₄),    separated, dried (MgSO₄), filtered and the solvent was evaporated.    The residue was purified by column chromatography over silica gel    (eluent: cyclohexane/EtOAc 85/1; 15–35 μm). The pure fractions were    collected and the solvent was evaporated, yielding 1 g of    [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl]-6-quinolinyl-methanone    (intermediate 28), melting point: 170° C.-   g) BuLi (0.0345 mol) was added dropwise at −70° C. to a solution of    1-methyl-1H-imidazole (0.0345 mol) in THF (30 ml) under N₂ flow. The    mixture was stirred for 15 minutes. Chlorotriethyl-silane (0.0354    mol) was added dropwise. The mixture was stirred at −70° C. for 15    minutes. BuLi (0.0305 mol) was added dropwise. The mixture was    stirred for 15 minutes. A solution of intermediate 28 (0.0197 mol)    in THF (85 ml) was added dropwise at −70° C. The mixture was stirred    at −70° C. for 1 hour, poured out into water, extracted with CH₂Cl₂    and washed with water. The organic layer was separated, dried    (MgSO₄), filtered, and the solvent was evaporated. The residue was    purified by column chromatography over silica gel (eluent:    CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 15–35 μm). The fractions were collected    and the solvent was evaporated. Yielding: 5.2 g (51%). A sample    (2.9 g) was crystallized from 2-propanone. The precipitate was    filtered off and dried, yielding 2.03 g of    2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(6-quinolinyl)-6-quinazolinemethanol    (intermediate 29), melting point 250° C.

EXAMPLE A5

-   a) BuLi (0.044 mol) was added dropwise at −70° C. to a solution of    5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.044 mol) in THF    (130 ml) under N₂ flow. The mixture was stirred at −70° C. for 15    minutes. A solution of    (6-chloro-3-pyridinyl)(1-methyl-1H-imidazol-5-yl)-methanone (0.028    mol) in THF (80 ml) was added dropwise. The mixture was stirred at    −70° C. for 1.5 hour, then poured out into water and extracted with    CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered,    and the solvent was evaporated. The residue was purified by column    chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1;    15–35 μm). The fractions were collected and the solvent was    evaporated. Yielding: 2.5 g (21%). A sample (0.9 g) was crystallized    from CH₃CN/diethyl ether. The precipitate was filtered off and    dried, yielding 0.85 g of    3-(3-chlorophenyl)-α-(6-chloro-3-pyridinyl)-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol    (intermediate 30), melting point 230° C.-   b) TiCl₃ 15% in water (23 ml) was added dropwise at 5° C. to a    mixture of intermediate 30) (0.0005 mol) in THF (23 ml). The mixture    was stirred at 5° C. for 5 hours, poured out into ice water,    basified with NaOH 3N and filtered over celite. The organic layer    was washed with water, separated, dried (MgSO₄), filtered and the    solvent was evaporated, yielding 1.5 g (66%) of    [2-amino-5-[(6-chloro-3-pyridinyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)-methanone    (intermediate 31).-   c) Trichloro-acetyl chloride (0.003 mol) then triethylamine (0.003    mol) were added dropwise at 5° C. to a mixture of intermediate 31    (0.003 mol) in dichloromethane (15 ml) under N₂ flow. The mixture    was stirred at room temperature for 5 hours, poured out into ice    water and extracted with CH₂Cl₂. The organic layer was separated,    dried (MgSO₄), filtered, and the solvent was evaporated, yielding    1.97 g (100%) of    2,2,2-trichloro-N-[2-(3-chlorobenzoyl)-4-[(6-chloro-3-pyridinyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl]-acetamide    (intermediate 32).

EXAMPLE A6

-   a) Trichloro-acetyl chloride (0.224 mol) was added dropwise at 5° C.    to a mixture of (2-amino-5-bromophenyl)(3-chlorophenyl)-methanone    (0.187 mol) in dichloromethane (520 ml). The mixture was stirred for    20 minutes. Triethylamine (0.224 mol) was added dropwise. The    mixture was stirred at room temperature for 1 hour and 30 minutes,    poured out into ice water and extracted with EtOAc. The organic    layer was separated, washed with water, dried (MgSO₄), filtered and    the solvent was evaporated, yielding 81 g (95%) of    N-[4-bromo-2-(3-chlorobenzoyl)phenyl]-2,2,2-trichloro-acetamide    (intermediate 33). The product was used without further purification    in the next reaction step.-   b) A mixture of intermediate 33 (0.160 mol) and acetic acid,    ammonium salt (0.320 mol) in dimethylsulfoxide (500 ml) was stirred    at 120° C. for 1 hour then cooled and poured out into ice water. The    precipitate was filtered, washed with water (4 liters) then with    acetonitrile and dried, yielding 42 g (79%). A part (1 g) of the    residue (84 g, 79%) was crystallized from CH₃CN/CH₃OH. The    precipitate was filtered off and dried, yielding 0.43 g of    6-bromo-4-(3-chlorophenyl)-2(1H)-quinazolinone (intermediate 34),    melting point 281° C.-   c) A mixture of intermediate 34 (0.06 mol) in phosphoryl chloride    (100 ml) was stirred and refluxed for 1 hour and 30 minutes then    cooled. The solvent was evaporated. The residue was taken up several    times in CH₂Cl₂. The solvent was evaporated, yielding 24 g    (quantitative) of 6-bromo-2-chloro-4-(3-chlorophenyl)-quinazoline    (intermediate 35). The product was used without further purification    in the next reaction step.-   d) CH₃OH (200 ml) was added slowly at 5° C. to intermediate 35 (0.06    mol). The mixture was stirred at 5° C. for 15 minutes. CH₃ONa/CH₃OH    (0.36 mol) was added dropwise slowly at 5° C. then brought to room    temperature, stirred and refluxed for 1 hour, cooled, poured out    into ice water and extracted with CH₂Cl₂. The organic layer was    separated, dried (MgSO₄), filtered, and the solvent was evaporated.    The residue (21 g) was crystallized from DIPE. The precipitate was    filtered off and dried, yielding 17.7 g (84%) of    6-bromo-4-(3-chlorophenyl)-2-methoxy-quinoline (intermediate 36),    melting point 132° C.-   e) A mixture of intermediate 36 (0.0315 mol), Pd(PPh₃)₄ (0.00315    mol) and N-methoxy-methanamine (0.069 mol) in triethylamine (22 ml)    and dioxane (100 ml) was stirred at 100° C. for 18 hours under a 5    bar pressure of CO, then cooled, poured out into ice water,    extracted with CH₂Cl₂ and filtered over celite. The organic layer    was separated, dried (MgSO₄), filtered and the solvent was    evaporated. The residue was purified by column chromatography over    silica gel (eluent: CH₂Cl₂/EtOAc 85/15 then CH₂Cl₂/CH₃OH/NH₄OH    98/2/0.4; 15–35 μm). The fractions were collected and the solvent    was evaporated, yielding 3 g (27%) of    4-(3-chlorophenyl)-N,2-dimethoxy-N-methyl-6-quinazolinecarboxamide    (intermediate 37), melting point: 118° C.-   f) Phosphoryl chloride (0.084 mol) was added dropwise at room    temperature to a solution of intermediate 37 (0.042 mol) in DMF (110    ml). The mixture was stirred at 80° C. for 4 hours, cooled, poured    out into ice water, extracted with EtOAc and basified with K₂CO₃    solid. The organic layer was separated, dried (MgSO₄), filtered, and    the solvent was evaporated. The residue was crystallised from DMF.    The precipitate was filtered off and dried. Part (0.15 g) of the    residue (9 g/59%) was dried at 90° C. under a vacuum, yielding 0.12    g of    2-chloro-4-(3-chlorophenyl)-N-methoxy-N-methyl-6-quinazolinecarboxamide    (intermediate 38), melting point 110° C.-   g) BuLi 1.6M in hexane (0.042 mol, 26.2 ml) was added dropwise at    −70° C. to a mixture of 1-methyl-1H-imidazole (0.042 mol) in THF    (80 ml) under N₂ flow. The mixture was stirred for 15 minutes.    Chlorotriethyl-silane (0.043 mol) was added. The mixture was stirred    for 15 minutes. BuLi 1.6M in hexane (0.037 mol, 23.2 ml) was added    at −70° C. The mixture was stirred for 15 minutes. A solution of    intermediate 38 (0.024 mol) in THF (80 ml) was added at −70° C. The    mixture was stirred at −70° C. for 30 minutes, poured out into water    and extracted with EtOAc. The organic layer was separated, dried    (MgSO₄), filtered, and the solvent was evaporated. The residue    (13 g) was purified by column chromatography over silica gel    (eluent: CH₂Cl₂/CH₃OH 97/3; 15–35 μm). Two fractions were collected    and the solvent was evaporated, yielding 1.4 g F1 and 2.4 g F2 Each    fraction was purified by column chromatography over silica gel    (eluent: CH₂Cl₂/EtOAc 50/50 then CH₂Cl₂/CH₃OH 97/3; 15–40 μm). The    fractions were collected and the solvent was evaporated, yielding    2.46 g (27%) of    [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](1-methyl-1H-imidazol-5-yl)-methanone    (intermediate 39), melting point: 190° C.-   h) A toluene solution (20%) of Hydrobis (2-methylpropyl)-aluminum    (10 ml) was added dropwise at −70° C. to a mixture of intermediate    39 (0.012 mol) in THF (150 ml) under N₂ flow. The mixture was    stirred at −70° C. for 30 minutes. Hydrobis(2-methylpropyl)-aluminum    (50 ml) was added. The mixture was stirred at −70° C. for 3 hours,    poured out into ice water, extracted with CH₂Cl₂ and filtered over    celite. The organic layer was separated, dried (MgSO₄), filtered,    and the solvent was evaporated, yielding 4 g (86%) of    2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol    (intermediate 40), melting point 140° C.-   i) NaN₃ (0.031 mol) was added at room temperature to a mixture of    intermediate 40 (0.0103 mol) in DMF (40 ml). The mixture was stirred    at 90° C. for 4 hours, then cooled, poured out into ice water and    stirred at room temperature for 1 hour. The precipitate was filtered    off and dried at 80° C. under a vacuum, yielding 3.4 g (84%) of    5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol    (intermediate 41), melting point 190° C.-   j) A mixture of intermediate 41 (0.0025 mol) in thionyl chloride    (10 ml) was stirred at 65° C. for 4 hours, then cooled and the    solvent was evaporated till dryness. The residue was taken up twice    in CH₂Cl₂. The solvent was evaporated till dryness, yielding    7-[chloro(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinazoline    as a hydrochloride salt (intermediate 42).

B. PREPARATION OF THE FINAL COMPOUNDS EXAMPLE B1

A mixture of intermediate 8 (0.0040 mol) and sodium azide (0.0119 mol)in DMF (40 ml) was stirred at 90° C. for 3 hours, cooled and poured outinto ice water. The precipitate was filtered. The filtrate was extractedwith CH₂Cl₂. The organic layer was brought together with the precipitatedissolved in CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue was crystallizedfrom CH₃CN/DIPE. The precipitate was filtered off and dried, yielding1.33 g (66%) of5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-)tetrazolo[1,5-a]quinazoline-7-methanol(compound 1), melting point: 202° C.

EXAMPLE B2

Sodium nitrite (0.00025 mol) was added at 5° C. to a mixture of nitricacid (0.5 ml) in water (0.5 ml). A solution of intermediate 19 (0.00025mol) in THF (1.5 ml) was added dropwise at 5° C. The mixture was stirredat 5° C. for 30 minutes, poured out into ice water, basified with K₂CO₃10% and extracted with EtOAc. The organic layer was washed with H₂O,separated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 100/0 to 90/10; 10 μm). The pure fractions were collectedand the solvent was evaporated, yielding 0.04 g (33%) of4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone(compound 2) MS (MH⁺):496, 498, 500.

EXAMPLE B3

-   a) A mixture of intermediate 22 (0.0022 mol) and NaN₃ (0.0066 mol)    in DMF (10 ml) was stirred at 140° C. for 3 hours, cooled, poured    out into water and stirred. The precipitate was filtered, washed    with water, then with diethyl ether and dried. The residue (0.94 g,    93%) was crystallized from 2-propanone. The precipitate was filtered    off and dried, yielding 0.75 g (74%) of    5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanol    (compound 3), melting point: 188° C.-   b) Compound 3 (0.00131 mol) was added at 5° C. in thionyl chloride    (6 ml). The mixture was stirred at room temperature for 2 hours.    Thionyl chloride was evaporated. The residue was taken up in CH₂Cl₂.    The solvent was evaporated till dryness, yielding (100%) of    7-[chloro-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a]quinoline    (compound 4). The product was used without further purification.-   c) NH₃/iPrOH (6 ml) was added dropwise at 5° C. to a solution of    compound 4 (0.00131 mol) in THF (6 ml). The mixture was stirred at    room temperature for 3 hours, poured out into water and extracted    with EtOAc. The organic layer was separated, dried (MgSO₄),    filtered, and the solvent was evaporated. The residue (0.6 g) was    purified by column chromatography over silica gel (eluent:    CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.5; 15–40 μm). The pure fractions were    collected and the solvent was evaporated, yielding 0.2 g (33%) of    5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinoline-7-methanamine    (compound 5) MS (MH⁺):455, 457.

EXAMPLE B4

-   a) A mixture of intermediate 29 (0.005 mol) in HCl 6N (50 ml) was    stirred and refluxed for 18 hours, then cooled. The solvent was    evaporated. The residue was taken up in a minimum of water, basified    with K₂CO₃. The precipitate was filtered, washed with water and    dried under a vacuo, yielding 2.5 g (100%) of    4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)-6-quinolinylmethyl]-2(1H)-quinazolinone    (compound 6).-   b) A solution of BTEAC (0.0005 mol) in NaOH (25 ml) then iodomethane    (0.006 mol) were added dropwise to a mixture of compound 6 (0.005    mol) in THF (25 ml). The mixture was stirred at room temperature for    24 hours, then poured out into water and extracted with CH₂Cl₂. The    organic layer was separated, dried (MgSO₄), filtered and the solvent    was evaporated. The residue was purified by column chromatography    over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 15–40 μm). The    fractions were collected and the solvent was evaporated, yielding:    0.656 g (26%) of    4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)-6-quinolinylmethyl]-1-methyl-2(1H)-quinazolinone    (compound 7), melting point: 192° C.

EXAMPLE B5

A mixture of intermediate 8 (0.0007 mol) in HCl 3N (5 ml) was stirredand refluxed for 30 minutes. The solvent was evaporated. The residue wastaken up in a minimum of water, basified with K₂CO₃, filtered, rinsedwith water and dried. The residue was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.2 to 50/50/1; 15–40μm). The pure fractions were collected and the solvent was evaporated,yielding 0.323 g (83.8%) of4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2(1H)-quinazolinone(compound 8) MS (MH⁺):482, 484, 486.

EXAMPLE B6

Ammonium acetate (0.006 mol) was added to a mixture of intermediate 32(0.003 mol) in dimethylsulfoxide (20 ml). The mixture was stirred at 60°C. for 4 hours, then cooled, poured out into ice water and filtered. Theprecipitate was taken up in CH₂Cl₂/toluene, filtered off and dried undera vacuo, yielding 0.66 g (42%) of4-(3-chlorophenyl)-6-[(6-chloro-3-pyridinyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2(1H)-quinazolinone(compound 9) MS (MH⁺):477, 479, 481.

EXAMPLE B7

2-Phenyl-1H-imidazole (0.0038 mol) was added at room temperature to amixture of intermediate 42 (0.0025 mol) in acetonitrile (10 ml). Themixture was stirred and refluxed for 2 hours, poured out into ice waterand extracted with CH₂Cl₂/CH₃OH. The organic layer was washed withK₂CO₃, separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2; 15–40 μm). The purefractions were collected and the solvent was evaporated. The residue(0.2 g) was dried at 80° C. for 3 hours, yielding 0.17 g (13%) of,5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-tetrazolo[1,5-a]quinazoline(compound 10), melting point: 150° C.

Table F-1 lists the compounds that were prepared according to one of theabove Examples. The following abbreviations were used in the tables:

TABLE F-1

Co. No. 11; Ex. B1; mp. 232° C.

Co. No. 12; Ex. B1; mp. 188° C.

Co. No. 13; Ex. B1; mp. 228° C.

Co. No. 14; Ex. B1; mp. 200° C.

Co. No. 15; Ex. B1; mp. 245° C.

Co. No. 16; Ex. B1; mp. 192° C.

Co. No. 17; Ex. B3; mp. 220° C.

Co. No. 18; Ex. B3; MS (MH⁺): 505, 507

Co. No. 19; Ex. B3; MS (MH⁺): 500, 502 504

Co. No. 20; Ex. B4; mp. 160° C.

Co. No. 21; Ex. B1; mp. 210

Co. No. 22; Ex. B1; mp. 218° C.

Co. No. 23; Ex. B1; mp. 242° C.

Co. No. 24; Ex. B1; mp. 192° C.

Co. No. 25; Ex. B1; mp. 190° C.

Co. No. 26; Ex. B1; mp. 200° C.

Co. No. 27; Ex. B3; MS (MH⁺): 506, 508

Co. No. 28; Ex. B7; mp. 120° C.

Co. No. 29; Ex. B1; mp. 220° C.

Co. No. 30; Ex. B7; mp. 154° C.

Co. No. 31; Ex. B3; mp. 254° C.

Co. No. 32; Ex. B7; mp. 148° C.

Co. No. 33; Ex. B1; mp. 178° C.

Co. No. 34; Ex. B7; mp. 177° C.

Co. No. 35; Ex. B7; MS (MH⁺): 542, 544

Co. No. 36; Ex. B7; MS (MH⁺): 468, 470

Co. No. 37; Ex. B3; mp. 208° C.

C. PHARMACOLOGICAL EXAMPLE EXAMPLE C.1 In Vitro Assay for Inhibition ofFarnesyl Protein Transferase

An in vitro assay for inhibition of farnesyl transferase was performedessentially as described in WO 98/40383, pages 33–34.

EXAMPLE C.2 Ras-transformed Cell Phenotype Reversion Assay

The ras-transformed cell phenotype reversion assay was performedessentially as described in WO 98/40383, pages 34–36.

EXAMPLE C.3 Farnesyl Protein Transferase Inhibitor Secondary Tumor Model

The farnesyl protein transferase inhibitor secondary tumor model wasused as described in WO 98/40383, page 37.

D. COMPOSITION EXAMPLE Film-coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere are added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of a compound of formula(I).

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinyl-pyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or N-oxide or stereochemicallyisomeric form thereof, wherein r is 0 or 1; >Y¹—Y² — is a trivalentradical of formula>C═N-(y-1); R¹ is halo; R² is a thiophene, furyl, pyridyl, diazolyl,oxazolyl, benzodiazolyl, benzotriazolyl, or quinolinyl group, optionallysubstituted by halo, cyano, C₁₋₆alkyl, or aryl; R³ is hydrogen, or aradical of formula—O—R¹⁰  (b-1) or—NR¹¹R¹²  (b-3); wherein R¹⁰ R¹¹ and R¹² are hydrogen; and R¹² ishydrogen or hydroxyl; R⁴ is a radical of formula

wherein R¹⁶ is hydrogen; R¹⁷ is C₁₋₆alkyl; R¹⁸ is C₁₋₆alkyl; R^(18a) ishydrogen; R⁵ is C₁₋₆alkyl, —CH₂—C₃₋₁₀cycloalkyl-, —C₁₋₆alkyl-Ar²; R⁷ isoxygen; or R⁶ and R⁷ together form a trivalent radical of formula:—CR³⁰═N—N═  (x-2)or—N═N—N═  (x-4) wherein R³⁰ is hydrogen; Ar is phenyl, or phenylsubstituted by one to five substituents each independently selected fromhalo, hydroxy, cyano, nitro, C₁₋₆alkyl, haloC₁₋₆alkyl, -alkylNH²,C₁₋₆alkyloxy, OCF₃, hydroxycarbonyl, C₁₋₆alkyloxycarbonyl, or a bivalentsubstituent of formula —O—CH₂—O— or —O—CH₂—CH₂—O—.
 2. The compound ofclaim 1 in which r is 1; R² is a 4-chloro-thiophen-2-yl, 3-furyl,5-chloro-pyrid-3-yl, 2-phenyl-imidazol-1-yl, 2-ethyl-imidazol-1-yl,benzimidazol-1-yl or 2-hydroxy-quinoline-7-yl group; or R⁶ and R⁷together form a trivalent radical of forrnula —N═N—N═.
 3. A compoundselected from:5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol,5-(3-chlorophenyl)-α-(3-furanyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo-[1,5-a]quinazoline-7-methanol,5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(6-quinolinyl)-tetrazolo-[1,5a]quinazoline-7-methanol,5-(3-chlorophenyl)-α-(5-chloro-2-thienyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine,4-(3-chlorophenyl)-6-[(5-chloro-2-thienyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]1-methyl-2(1H)-quinazolinone,5-(3-chlorophenyl)-7-[(1-methyl-1H-imidazol-5-yl)(2-phenyl-1H-imidazol-1-yl)methyl]-tetrazolo[1,5-a]quinazoline,α-(2-benzofuranyl)-5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine,5-(3-chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline, 5-(3-chlorophenyl)-α,α-bis(1-methyl-1H-imidazol-5-yl)-tetrazolo[-1,5-a]quinazoline-7-methanol,5-(3-chlorophenyl)-7-[[2-(4-fluorophenyl)-1H-imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo[1,5-a]quinazoline,3-[1-[[5-(3-chlorophenyl)tetrazolo[1,5-a]quinazolin-7-yl](1-methyl-1H-imidazol-5-yl)methyl]-1H-imidazol-2-yl]-benzonitrile,and their pharmaceutically acceptable salts.
 4. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier, and anactive ingredient comprising a therapeutically effective amount of acompound of claim
 1. 5. A pharmaceutical composition comprising apharmaceutically acceptable carrier, and an active ingredient comprisinga therapeutically effective amount of a compound of claim
 2. 6. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier, and an active ingredient comprising a therapeutically effectiveamount of a compound of claim
 3. 7. A method for treating colon andpancreatic carcinomas comprising administering an effective amount of acompound according to claim 1 to a subject in need of such treatment. 8.A method for treating colon and pancreatic carcinomas comprisingadministering an effective amount of a compound according to claim 2 toa subject in need of such treatment.
 9. A method for treating colon andpancreatic carcinomas comprising administering an effective amount of acompound according to claim 3 to a subject in need of such treatment.